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First published online April 23, 2007
doi: 10.1242/10.1242/jcs.003129

Journal of Cell Science 120, 1646-1653 (2007)
Published by The Company of Biologists 2007
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Research Article

TGFbeta3 inhibits E-cadherin gene expression in palate medial-edge epithelial cells through a Smad2-Smad4-LEF1 transcription complex

Ali Nawshad1,*,{ddagger}, Damian Medici2,*, Chang-Chih Liu1 and Elizabeth D. Hay2

1 Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583, USA
2 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA

{ddagger} Author for correspondence (e-mail: anawshad{at}unmc.edu)

Accepted 5 March 2007

Dissociation of medial-edge epithelium (MEE) during palate development is essential for mediating correct craniofacial morphogenesis. This phenomenon is initiated by TGFbeta3 upon adherence of opposing palatal shelves, because loss of E-cadherin causes the MEE seam to break into small epithelial islands. To investigate the molecular mechanisms that cause this E-cadherin loss, we isolated and cultured murine embryonic primary MEE cells from adhered or non-adhered palates. Here, we provide the first evidence that lymphoid enhancer factor 1 (LEF1), when functionally activated by phosphorylated Smad2 (Smad2-P) and Smad4 (rather than beta-catenin), binds with the promoter of the E-cadherin gene to repress its transcription in response to TGFbeta3 signaling. Furthermore, we found that TGFbeta3 signaling stimulates epithelial-mesenchymal transformation (EMT) and cell migration in these cells. LEF1 and Smad4 were found to be necessary for up-regulation of the mesenchymal markers vimentin and fibronectin, independently of beta-catenin. We proved that TGFbeta3 signaling induces EMT in MEE cells by forming activated transcription complexes of Smad2-P, Smad4 and LEF1 that directly inhibit E-cadherin gene expression.

Key words: E-cadherin, LEF1, Smad, TGF-beta, Epithelial-m






© The Company of Biologists Ltd 2007